Amblyopia
Amblyopia is a clinical condition which is characterized by a dysfunction in the processing of visual information. Typically, it is detected as reduced visual acuity in the absence of pathological findings in the opthalmological examination. Amblyopia results from abnormal processing of visual information in the visual cortex due to reduced or imbalanced use of eyes during a critical period of postnatal development. Most often, strabismus, anisomeropia or visual deprivation in one eye during the first years leads to permanent reduction in vision acuity in the affected eye (Holmes and Clarke, 2006). Amblyopia is the most common cause of monocular vision loss with the prevalence in children of 1-5% and in adults about 3% (Holmes and Clarke, 2006). Adult amblyopics show impaired depth perception due to the lack of stereovision and are at a significantly increased risk of blindness if vision in the better eye is lost due to accident or disease. Amblyopia can be prevented if the use of the weaker eye is encouraged during childhood by optical or pharmaceutical occlusion of the better eye. However, occlusion therapy only works during a critical period of postnatal development; after the gradual closure of the critical period in adolescence, in humans typically by the age of 10 years, occlusion no longer helps and amblyopia remains permanent.
Experimental research using experimental animals, such as monkeys, cats, rats and mice has over several decades revealed the neurobiological processes underlying amblyopia (Berardi et al., 2003). During early postnatal development, inputs from left and right eye compete for the innervation of the visual cortex and in the case of normal vision in both eyes, the mammalian visual cortex organises into eye-specific columns known as ocular dominant (OD) columns, which represent morphological and functional segregation of inputs from each eye into the layer IV of the primary visual cortex. The proper innervation of the visual cortex requires balanced visual input through both eyes (Berardi et al., 2003). Hence, if the other eye is closed during the early postnatal development and kept closed to adulthood, the open eye takes over the deprived eye and gradually innervates almost the entire primary visual cortex, while the deprived eye looses its connectivity with the neurons in the visual cortex both anatomically and physiologically. This reorganization takes place most effectively during a critical period during the postnatal development, which lasts for between a few days to few years, depending on the species and leads to the greatly impaired visual acuity of the deprived eye (Berardi et al., 2003). After the closure of the critical period, in adulthood, closure of the other eye will not significantly affect the visual acuity of the closed eye and the already established anatomical and physiological segregation into OD columns in the brain and, conversely, an eye deprived during the critical period will not improve its visual acuity or regain the lost anatomical or physiological connectivity, if opened in adulthood. It has been demonstrated that the increase and maturation of the gamma-aminobutyric acid (GABA)-mediated neuronal inhibition in the visual cortex is a critical factor which brings about the closure of the critical period during development (Berardi et al., 2003). In conclusion, even though amblyopia develops as a consequence of a problem in the eye (strabismus, anisomeropia or visual deprivation), after the end of the critical period amblyopia is no longer an eye problem, it is a problem of the neuronal connections between the eye and the visual cortex. Any measures which correct the underlying developmental problem in the eye (such as operative treatment of strabismus) after the closure of the critical period, have not been shown to improve the visual acuity of the amblyopic eye.
Currently, there are no pharmacological interventions which could help to regain or improve vision in the deprived eye in adulthood, after the closure of the critical period (Holmes and Clarke, 2006). Occasional open-label clinical trials with L-DOPA and Citocholine have suggested that pharmacological treatments might improve vision in adult amblyopics (Campos and Fresina, 2006), but the side effects of these drugs have prevented their use. Methods have been proposed where the pharmacological agents are used to influence the growth of eyes during development; abnormal eye growth during early development may produce anisomeropia and therefore lead to the development of amblyopia (WO 9425034 A1; WO 0152832 A1; WO 03032975 A1; U.S. Pat. Nos. 5,567,731 A; 5,571,823 A; US 2003114830 A1). However, since amblyopia is a disorder of the connectivity between the eye and the brain, any means which influences eye growth will not ameliorate the lost neuronal connectivity of the amblyopic eye in the visual cortex after the closure of the critical period. Intracortical injection of an enzyme (Chondroitinase ABC), which degrades extracellular matrix has been shown to reinstate critical period plasticity in adult rat brain, but the enzyme needs to be injected at several locations directly into the visual cortex (Pizzorusso et al., 2002; Pizzorusso et al., 2006). A treatment which could improve the vision in the amblyopic eye in adulthood would be very welcome, in particular in those cases where the vision of the better eye is lost after the closure of the critical period.
Antidepressant Drugs
Drugs which are clinically used to treat symptoms of depression and mood disorders in humans are called antidepressant drugs or antidepressants. Most of the clinically active antidepressants increase the synaptic concentrations of monoamine transporters serotonin (5-hydroxytryptamine, 5-HT) or norepinephrine (NE) by either inhibiting their reuptake into cells (reuptake inhibitors) or by inhibiting monoamine oxidase (MAO), which degrades these transmitters (monoamine oxidase inhibitors, MAOI). Reuptake inhibitors are subdivided into tricyclic antidepressants, serotonin selective reuptake inhibitors (SSRI) and NE-selective reuptake inhibitors (NSRI). Serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of both serotonin and norepinephrine into cells. Among antidepressants, the SSRIs are the most widely used drug class, largely due to the fact that they produce relatively few side effects. Among the SSRIs, fluoxetine is one of the most widely used drugs. Clinical experience of over 50 years indicates that all known antidepressant drugs need to be administered repeatedly over a period of at least several weeks for the clinical efficacy.
Antidepressants and Neuronal Plasticity
Neuronal plasticity refers to the ability of neurons to modify their connectivity by either forming new neurons or synaptic contacts or withdrawing existing contacts, or by potentiating or depressing the strength of the existing synaptic contacts. The neurotrophic factor Brain-derived neurotrophic factor (BDNF) is a critical regulator of neuronal plasticity in both developing and adult brain. Evidence accumulated over the last decade suggests that antidepressant drugs are involved in the regulation of neuronal plasticity (Castrén, 2004). Antidepressant drugs increase the production of new neurons in the hippocampal dentate gyrus and increase axonal sprouting and synaptogenesis in hippocampus. Antidepressant treatments also increase the expression of plasticity-related genes and proteins in the hippocampus (Castrén, 2004). Specifically, representatives of all the known antidepressant classes increase the production of the mRNA for BDNF when administered repeatedly and activate the BDNF receptor trkB, as measured by increased trkB autophosphorylation, after either a single or repeated administration (Castrén, 2004). BDNF and its receptor trkB are critical mediators of neuronal plasticity and they also appear to be critical mediators of the efficacy of antidepressant drugs at least in rodents.